The identity of endothelium-derived relaxing factor (EDRF) is still debated, but several workers believe that it is identical to nitric oxide (NO). Several important drugs such as glyceryl trinitrate (GTN), sodium nitroprusside (SNP) and hydrolazine and some xenobiotics of toxicological or environmental concern including sodium azide, hydroxylamine hydrochloride and sodium nitrate mimic the biological effects of EDRF and NO. It is presumed that these chemicals owe their biological activity to biotransformation to NO in vivo. The proposed research will study the mechanism(s) by which these biotransformations occur. A goal is to screen blood samples from normal human subjects and from subjects who are hypersensitive but receiving drugs other than NO-vasodilators in the hope of obtaining evidence for endogenous NO in for form of EPR signals from NO-hemoglobins. Plans are also to examine blood samples from patients receiving NO-vasodilators for therapeutic purposes, and blood from animals given drugs known to act through EDRF such as acetylcholine, histamine, serotonin and bradykinin. An aim is to study the decomposition of SNP by cyclic voltammetry, and during its reactions with hemoglobin, methemoglobin and glutathione and characterize the intermediate products by EPR. The stability of these intermediates will be examined in the presence of cyanide. Cyanide stabilization of a particular intermediate may explain its ability to block the effects of SNP. The reactions of azide, hydrozylamine, nitrite, hydralazine and SNP with catalase will be studied to ascertain if NO is liberated and if catalase inhibitors block the reaction. There are also plans to continue pilot studies on sulfur transferases as they are involved in cyanide biotransformation. The major objective is to clarify the metabolism and mechanism of action of NO-vasodilator drugs and poisons with two goals in mind: to elucidate the mechanism(s) by which tolerance develops to such drugs as GTN and to find ways to intercede in poisonings.